從路易氏體失智症之病理特徵找尋治療方法

Exploring a Therapeutic Method for Dementia with Lewy Bodies Based on the Pathophysiology

何應瑞(Ying-Jui Ho) ； 許弘毅(Hung-Yi Hsu) ； 張鳴宏(Ming-Hon Chang) ； 廖玟潔(Wen-Chieh Liao) ； 林志立(Chih-Li Lin) ； 洪菁穗(Ching-Sui Hung)

《台灣醫學》 23卷3期 (2019/05) Pp. 376-383

https://doi.org/10.6320/FJM.201905_23(3).0011

摘要

路易氏體失智症（dementia with Lewy bodies, DLB）是許多神經退化性疾病中的一種，雖然這些疾病的症狀各異，但是具有如下的共同病理特徵：（1）α-突觸核蛋白（α-synuclein; α-syn）與β-amyloid（Aβ）交互作用生成路易氏體堆積，（2）麩胺酸（glutamate）過多引發神經毒性。頭孢曲松（ceftriaxone, CEF）過去長期作為抗生素治療感染性疾病之用，具有相當高的安全性。近年許多研究證實CEF具有下列功能：（1）可以與α-syn穩定結合，抑制其形成聚合物堆積；（2）啟動調節Aβ新陳代謝之相關基因，一方面抑制生成之基因，同時活化其分解之基因；（3）增加麩胺酸轉運蛋白（glutamate transporter-1, GLI-1）之表現，清除麩胺酸，降低興奮性毒性；（4）促進神經新生（neurogenesis），修復神經密度。上述效果均顯示CEF有利於治療神經退化性疾病，因此值得推動使用CEF治療DLB之臨床試驗，以驗證CEF在此疾病之效果。

關鍵字

神經退化性疾病 ； 路易氏體失智症 ； 頭孢曲松 ； 麩胺酸

並列摘要

Dementia with Lewy bodies (DLB) is one of the neurodegenerative disorders that have different symptoms but some common pathophysiological features, for example: (1) deposition of Lewy bodies produced by interactions of α-synuclein (α-syn) and β-amyloid (Aβ); (2) glutamate-induced excitotoxicity. Ceftriaxone (CEF) is an old and safe drug being used as antibiotic. Recent studies have demonstrated the following effects of CEF: (1) binding well with α-syn and inhibing of α-syn polymerization; (2) modulation of genes related to Aβ metabolism, suppressing synthesis but increasing degradation; (3) increasing glutamate transporter-1 and glutamate reuptake, but decreasing excitotoxicity; (4) enhancing neurogenesis and recovery of neuronal density These results suggest a potential of CEF in treating neurodegenerative disorders. Thus, it is worthy to conduct a clinical trial to evaluate effects of CEF in DLB.

並列關鍵字

neurodegenerative disorders ； dementia with Lewy bodies ； ceftriaxone ； glutamate

參考文獻

McKeith IG, Dickson DW, Lowe J, et al: Diagnosis and management of dementia with Lewy bodies: third report of the DLB Consortium. Neurology 2005;65:1863-72.

Goedert M, Spillantini MG, Del Tredici K, et al: 100 years of Lewy pathology. Nat Rev Neurol 2013;9:13-24.

Savica R, Grossardt BR, Bower JH, et al: Incidence of dementia with Lewy bodies and Parkinson disease dementia. JAMA Neurol 2013;70:1396-402.

Chiu PY, Tsai CT, Chen PK, et al: Neuropsychiatric Symptoms in Parkinson's Disease Dementia Are More Similar to Alzheimer's Disease than Dementia with Lewy Bodies: A Case-Control Study. PLoS One 2016;11:e0153989.

Campbell BC, Li Q-X, Culvenor JG, et al: Accumulation of insoluble α-synuclein in dementia with Lewy bodies. Neurobiol Dis 2000;7:192-200.